As a result of its unique structure, the cornea is the most important optical element in the eye, and the innervation is an important homeostatic mechanism for the maintenance of corneal health and transparency. As the most densely innervated epithelial surface in the body, the cornea is exquisitely sensitive to sensory stimulation. The innervation protects the cornea and eye from overt damage and it is metabolically integrated into the cellular functions of the cornea. The studies proposed in this research will continue to reveal this interrelationship at the ionic, molecular, and ultrastructural levels. A putative role for Ca2+ in transduction mechanisms of the intraepithelial axon terminals will be studied by substitution of other di- and trivalent ions and calcium blockers. Sodium channel modifiers will be used to determine the role of sodium inactivation on repetitive firing of receptor responses. Direct biophysical and molecular approaches to these sensory receptor membranes will be facilitated by isolation of these membranes by newly developed cellular separation techniques. Homeostatic control of epithelial function by the neuron is probably exerted through axonally transported substance. Radiolabled precursors and tracers will be used to determine uptake of lipids, proteins, and glycoproteins by epithelial cells. Denervation of the cornea alters its mitotic properties and the fundamental ability of this tissue to utilize choline, a membrane lipid precursor, will be studied. The innervation often responds to changes in the environment of the cornea, as well as to disease and aging, by sensory dysfunction. The loss of sensitivity in contact lens wear may be due to a lowered O2 supply; this will be studied neurophysiologically in the rabbit. Aging, which will be studied in the Fischer 344 rat, induces morphological alterations of the receptors which may change the flow of sensory information to the central nervous system. Moreover, the corneal innervation serves as a conduit for herpes simplex virus type 1 in the establishment of latency. The role of a neuronal signal in reactivation of HSV-1 from the trigeminal ganglion will be examined as will the transport of the virus by the nerves. These studies should help us to understand the homeostatic interactions of the cornea and its innervation and how these interactions serve to maintain the optical function of the cornea and the eye itself.